Non-nucleoside inhibitors of HCV polymerase NS5B. Part 3: Synthesis and optimization studies of benzothiazine-substituted tetramic acids
Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clear...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2009-10, Vol.19 (19), p.5648-5651 |
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| creator | de Vicente, Javier Hendricks, Robert T. Smith, David B. Fell, Jay B. Fischer, John Spencer, Stacey R. Stengel, Peter J. Mohr, Peter Robinson, John E. Blake, James F. Hilgenkamp, Ramona K. Yee, Calvin Zhao, Junping Elworthy, Todd R. Tracy, Jahari Chin, Elbert Li, Jim Lui, Al Wang, Beihan Oshiro, Connie Harris, Seth F. Ghate, Manjiri Leveque, Vincent J.P. Najera, Isabel Pogam, Sophie Le Rajyaguru, Sonal Ao-Ieong, Gloria Alexandrova, Ludmila Fitch, Bill Brandl, Michael Masjedizadeh, Mohammad Wu, Shao-yong Keczer, Steve de Voronin, Tatyana |
| description | Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.
Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core. |
| doi_str_mv | 10.1016/j.bmcl.2009.08.023 |
| format | Article |
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Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2009.08.023</identifier><identifier>PMID: 19700319</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Animals ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Antiviral Agents - chemical synthesis ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacokinetics ; Benzothiazine ; Binding Sites ; Biological and medical sciences ; Clearance ; Crystallography, X-Ray ; CYP 3A4 ; HCV ; Hepacivirus - drug effects ; Hepatitis C virus ; Medical sciences ; NS5B ; Pharmacology. Drug treatments ; Pyrrolidinones - chemical synthesis ; Pyrrolidinones - chemistry ; Pyrrolidinones - pharmacokinetics ; Rats ; Structure-Activity Relationship ; Tetramic acid ; Thiazines - chemistry ; Time dependent inactivation ; Viral Nonstructural Proteins - antagonists & inhibitors ; Viral Nonstructural Proteins - metabolism</subject><ispartof>Bioorganic & medicinal chemistry letters, 2009-10, Vol.19 (19), p.5648-5651</ispartof><rights>2009 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c447t-fe42a8a9fec1f483d97cc3e14f90532b220a0a24c29c33bd4892cb5ad71eb4a33</citedby><cites>FETCH-LOGICAL-c447t-fe42a8a9fec1f483d97cc3e14f90532b220a0a24c29c33bd4892cb5ad71eb4a33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X09011573$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22002000$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19700319$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>de Vicente, Javier</creatorcontrib><creatorcontrib>Hendricks, Robert T.</creatorcontrib><creatorcontrib>Smith, David B.</creatorcontrib><creatorcontrib>Fell, Jay B.</creatorcontrib><creatorcontrib>Fischer, John</creatorcontrib><creatorcontrib>Spencer, Stacey R.</creatorcontrib><creatorcontrib>Stengel, Peter J.</creatorcontrib><creatorcontrib>Mohr, Peter</creatorcontrib><creatorcontrib>Robinson, John E.</creatorcontrib><creatorcontrib>Blake, James F.</creatorcontrib><creatorcontrib>Hilgenkamp, Ramona K.</creatorcontrib><creatorcontrib>Yee, Calvin</creatorcontrib><creatorcontrib>Zhao, Junping</creatorcontrib><creatorcontrib>Elworthy, Todd R.</creatorcontrib><creatorcontrib>Tracy, Jahari</creatorcontrib><creatorcontrib>Chin, Elbert</creatorcontrib><creatorcontrib>Li, Jim</creatorcontrib><creatorcontrib>Lui, Al</creatorcontrib><creatorcontrib>Wang, Beihan</creatorcontrib><creatorcontrib>Oshiro, Connie</creatorcontrib><creatorcontrib>Harris, Seth F.</creatorcontrib><creatorcontrib>Ghate, Manjiri</creatorcontrib><creatorcontrib>Leveque, Vincent J.P.</creatorcontrib><creatorcontrib>Najera, Isabel</creatorcontrib><creatorcontrib>Pogam, Sophie Le</creatorcontrib><creatorcontrib>Rajyaguru, Sonal</creatorcontrib><creatorcontrib>Ao-Ieong, Gloria</creatorcontrib><creatorcontrib>Alexandrova, Ludmila</creatorcontrib><creatorcontrib>Fitch, Bill</creatorcontrib><creatorcontrib>Brandl, Michael</creatorcontrib><creatorcontrib>Masjedizadeh, Mohammad</creatorcontrib><creatorcontrib>Wu, Shao-yong</creatorcontrib><creatorcontrib>Keczer, Steve de</creatorcontrib><creatorcontrib>Voronin, Tatyana</creatorcontrib><title>Non-nucleoside inhibitors of HCV polymerase NS5B. Part 3: Synthesis and optimization studies of benzothiazine-substituted tetramic acids</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.
Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.</description><subject>Animals</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - chemical synthesis</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacokinetics</subject><subject>Benzothiazine</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Clearance</subject><subject>Crystallography, X-Ray</subject><subject>CYP 3A4</subject><subject>HCV</subject><subject>Hepacivirus - drug effects</subject><subject>Hepatitis C virus</subject><subject>Medical sciences</subject><subject>NS5B</subject><subject>Pharmacology. 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Part 3: Synthesis and optimization studies of benzothiazine-substituted tetramic acids</title><author>de Vicente, Javier ; Hendricks, Robert T. ; Smith, David B. ; Fell, Jay B. ; Fischer, John ; Spencer, Stacey R. ; Stengel, Peter J. ; Mohr, Peter ; Robinson, John E. ; Blake, James F. ; Hilgenkamp, Ramona K. ; Yee, Calvin ; Zhao, Junping ; Elworthy, Todd R. ; Tracy, Jahari ; Chin, Elbert ; Li, Jim ; Lui, Al ; Wang, Beihan ; Oshiro, Connie ; Harris, Seth F. ; Ghate, Manjiri ; Leveque, Vincent J.P. ; Najera, Isabel ; Pogam, Sophie Le ; Rajyaguru, Sonal ; Ao-Ieong, Gloria ; Alexandrova, Ludmila ; Fitch, Bill ; Brandl, Michael ; Masjedizadeh, Mohammad ; Wu, Shao-yong ; Keczer, Steve de ; Voronin, Tatyana</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c447t-fe42a8a9fec1f483d97cc3e14f90532b220a0a24c29c33bd4892cb5ad71eb4a33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Antibiotics. 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Part 3: Synthesis and optimization studies of benzothiazine-substituted tetramic acids</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2009-10-01</date><risdate>2009</risdate><volume>19</volume><issue>19</issue><spage>5648</spage><epage>5651</epage><pages>5648-5651</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.
Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>19700319</pmid><doi>10.1016/j.bmcl.2009.08.023</doi><tpages>4</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2009-10, Vol.19 (19), p.5648-5651 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - chemical synthesis Antiviral Agents - chemistry Antiviral Agents - pharmacokinetics Benzothiazine Binding Sites Biological and medical sciences Clearance Crystallography, X-Ray CYP 3A4 HCV Hepacivirus - drug effects Hepatitis C virus Medical sciences NS5B Pharmacology. Drug treatments Pyrrolidinones - chemical synthesis Pyrrolidinones - chemistry Pyrrolidinones - pharmacokinetics Rats Structure-Activity Relationship Tetramic acid Thiazines - chemistry Time dependent inactivation Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - metabolism |
| title | Non-nucleoside inhibitors of HCV polymerase NS5B. Part 3: Synthesis and optimization studies of benzothiazine-substituted tetramic acids |
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